The subject of the present invention is novel tyrosine derivatives which can be represented by the general formula (I) which is indicated below and in which: 
R1 and R2 are selected, independently, from hydrogen, an alkyl group having from 1 to 4 carbon atoms, a halogen group such as a fluoro, chloro or bromo group, the methoxy group, the cyano group or the trifluoromethyl group, and
R3 is selected, independently, from a phenyl or a 2 (or 3 or 4)-pyridyl group, unsubstituted or mono- or di-substituted with an alkyl or alkoxy group having from 1 to 4 carbon atoms, with a halogen group such as a fluoro or chloro group, with the trifluoromethyl group, with the cyano group, with the nitro group, with the amino group, or with the phenyl group, a 1 (or 2)-naphthyl group, a 2 (or 3)-indolyl group as such or N-alkylated with an alkyl group having from 1 to 3 carbon atoms, a 2 (or 3, 4, 5, 6, 7 or 8)-quinolinyl or a 1 (or 3, 4, 5, 6, 7 or 8)-isoquinolinyl group, unsubstituted or mono- or di-substituted with a group selected, independently, from the methyl, ethyl, propyl, isopropyl, methoxy, fluoro, chloro, trifluoromethyl, cyano, amino, or nitro groups, a 2 (or 5 or 6)-quinoxalyl group, a 3 (or 4, 5, 6, 7 or 8) cinnolyl group, or a 2 (or 4, 5, 6 or 7)-benzimidazolyl group.
The configuration of the chiral centre marked with an asterisk (*) in the general formula (I) may be, independently, L, D or DL (racemic).
Preferably, R1 is hydrogen group, R2 is hydrogen or the 7-methyl or 7-fluoro group, and R3 is the 2-quinolinyl group or the 3-isoquinolinyl group.
The compounds of the present invention have been found to be potent receptor antagonists of the cysteinyl-leukotrienes (or LTD4 peptidyl-leukotrienes, hereinafter referred to as leukotrienes).
The leukotrienes are synthesized xe2x80x9cde novoxe2x80x9d from arachidonic acid associated with cell membranes. They are produced by a wide variety of inflammatory cells such as mast cells, basophils, eosinophils and macrophages. These compounds are considered to be amongst the principal chemical mediators inducing bronchial asthma in man; this seems fully justified by the fact that the pulmonary parenchyma, epithelium and bronchial smooth musculature in man are particularly rich in leukotriene receptors. The receptor stimulation induced by the peptide leukotrienes brings about an immediate contraction of the smooth musculature and increases mucous secretion by the epithelial cells. The compounds of the present invention may therefore be considered usable to advantage in the treatment of various diseases in man which are induced by leukotriene hyper-stimulation such as, for example, bronchial asthma, obstructive lung diseases, hay fever and rhinitis, in the respiratory tract, as well as in allergic conjunctivitis or in other pathological conditions of other organs or regions such as, for example, ulcerative colitis, Crohn""s disease, or food allergies and intolerances in the gastrointestinal system, or in the treatment of inflammatory or atherosclerosis-based pathological conditions of the cardiovascular system which are sensitive to leukotriene inhibition.
In addition to the leukotriene receptor antagonists which have recently started to be used for the treatment of asthma, such as montelukast (EP 480717 B1), pranlukast (U.S. Pat. No. 4,780,469) and zafirlukast (U.S. Pat. No. 4,859,692), many publications and patents describe novel compounds with anti-leukotriene activity. Thus, for example, U.S. Pat. No. 5,508,408 describes quinoline derivatives having leukotriene-antagonistic activity, amongst which is the compound iralukast (CGP 45715A), European patent 335 315 B1 describes alkanophenone derivatives, and patent WO 96/33181 describes ethinylthiazole derivatives. A monographic work published in J. Med. Chem. (1996), 39 (2629-2654), also describes the chemical structures and the pharmacological activities of numerous cysteinyl-leukotriene receptor antagonists amongst which, in addition to those already mentioned, are also others such as, for example, the compounds tomelukast, sulukast, ritolukast, verlukast and ablukast. Recently, a monographic work has been published on two antagonists which are structurally correlated with the receptor agonists, that is, pobilukast and SKF 106203, (Novel inhibitors of leukotrienes, G. Folco, B. Samuelsson, R. C. Murphy, Eds., Birkhxc3xa4user Verlag, 1999, p. 317). All of this research demonstrates that there is a great therapeutic need to find novel, ever more potent, selective and better tolerated drugs with leukotriene-antagonistic activity. In accordance with this need, the object of the present invention is to make available for therapy novel drugs having a potent and selective leukotriene-antagonist activity for the treatment of all pathological conditions in which a high degree of synthesis and liberation of peptide leukotrienes may assume a primary role, as in the case of allergic diseases in general and of bronchial asthma in particular.
Pharmaceutical forms of the compounds of the invention can be prepared by conventional techniques, for example, as tablets, capsules, suspensions, solutions, aerosols, or patches and can be administered by oral, parenteral, inhalational, transdermal or transmucosal routes, or in other forms suitable for achieving the therapeutic effect such as, for example, delayed-action solid preparations for oral use which permit controlled release of the active substance over time.
The active ingredient is normally administered to the patient with a reference dose variable from 0.01 to 1 mg/kg of body weight per dose. For parenteral administration; the use of a water-soluble salt of the compounds of the invention, such as the sodium salt, or another non-toxic and pharmaceutically acceptable salt is preferable. For the inhalational route, the administration of a water-soluble salt such as, for example, the sodium salt, is also preferable; moreover for this route it is preferable to dispense the active ingredient in the form of a fine, micronized powder having a mean particle diameter preferably of between 1 and 3 microns.
As inactive ingredients, substances commonly used in pharmaceuticals, such as excipients, binders, flavourings, disaggregrants, substances for stimulating transdermal and transmucosal absorption, colourings, humectants, etc., may be used and, for dispensing by means of a pressurized aerosol for inhalation, ecologically acceptable propellants or mixtures of propellants are also used.
The method for the preparation of the derivatives of the invention consists of a series of reactions which comprise:
a) reacting methyl tyrosine ester in the desired configuration with the aromatic or heterocyclic acid of formula (V):
R3xe2x80x94COOHxe2x80x83xe2x80x83(V)
xe2x80x83in which R3 has the meaning given above, by the mixed anhydride method, in an inert anhydrous solvent and at a temperature of between xe2x88x925xc2x0 C. and +15xc2x0 C., to give the N-acyl tyrosine derivatives of formula (IV) (see the general synthesis scheme, step 1);
b) reacting the compounds of formula (IV) with the halogenomethyl quinoline of formula (III): 
xe2x80x83in which R1 and R2 have the meanings given above and X may be chloro or bromo, in the presence of a base such as, for example, potassium carbonate, in an inert solvent such as, for example N,N-dimethyl formamide (DMF), and at a temperature of between 20xc2x0 C. and the reflux temperature of the solvent used, to give the esters of formula (II), in which R1, R2 and R3 have the meanings given above (see the general synthesis scheme, step 2);
c) hydrolyzing the esters of formula (II): 
xe2x80x83dissolved in an inert solvent such as, for example, methanol, with an inorganic base such as, for example, sodium hydroxide, in a molar ratio of from 1 to 1.5, to give the corresponding final derivatives of formula (I) in which R1, R2 and R3 have the meanings given above, according to the general synthesis scheme, step 3.
The aromatic or heterocyclic acids of formula (V), as well as the halogenomethyl quinoline of formula (III), are commercially available or are prepared by conventional methods in accordance with existing literature.
The final derivatives of formula (I) are obtained in the L, D or DL (racemic) forms, according to whether the starting compound was L, D or DL tyrosine.
General Synthesis Scheme (Scheme 1) 